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Battling A Brain Tumor The Loki Way

Recently a friend of mine took on the duty of bringing me up to speed on the Marvel cinematic universe. When we got around to watching the first installment in the Thor series, I was expecting more levelheadedness on the part of Thor, the soon-to-be crowned king of Asgard. Shortly after the opening sequence however, we were faced with an extremely volatile Thor who was single-mindedly driven to destroy the Frost Giants of Jotunheim for daring to enter Asgard. His rash behavior that followed and the unsuccessful outcome of his mission led to his banishment from Asgard and set the stage for his brother Loki to use deceptive tactics to ultimately slay Laufey, the leader of Jotunheim. In medicine, there are many cases in which a sledgehammer (or shall I say a “Mjölnir hammer”) approach to fighting a formidable disease does not yield favorable outcomes. Often, the scientific advancements that offer a more promising method of treatment are quite clever in how they utilize a biological trick to ensure that the treatment does more good than harm.

Cancer has been a difficult disease to treat to say the least, and though there has been an official urgency to understand the disease in its many forms since President Nixon signed the National Cancer Act in 1971, there are some cancer types that still have very low survival rates (e.g. glioblastoma, a type of brain tumor). This is why I was quite intrigued when I read a recent clinical case study of a 50-year-old man who had very aggressive and recurrent glioblastoma that responded positively to CAR T-cell therapy (Brown et al, 2016). This new therapy sounded like a more targeted approach than traditional chemotherapy which involves systemically introducing toxic chemicals that act on all rapidly replicating cells: cancer cells, hair cells, cells that line the digestive tract, cells in the bone marrow… Mjölnir style.

What is CAR T-cell therapy and how can it be a powerful addition to existing immunotherapy options for cancer?

Admittedly, among cancer treatment options, I was only aware of surgical removal of tumors, chemotherapy, and radiation treatment, which are currently the standard-of-care and what the 50-year-old patient in question initially received. Six months after standard-of-care therapy however, the cancer recurred in the patient’s brain, and the odds did not seem to be in his favor. At this point, the patient enrolled in a clinical study testing Chimeric Antigen Receptor T-cell therapy, CAR T-cell therapy for short. This was a fairly new technology that had been successful in some hematologic (blood) cancers; so successful in fact, that in August of 2017, not long after this clinical study was published, the FDA would approve the first CAR T-cell therapy for the treatment of acute lymphoblastic leukemia. One month later, this would be followed by the second FDA approved CAR T-cell therapy for certain types of non-Hodgkin lymphoma.

As part of the clinical study, the tumors that recurred were surgically removed and, across six weeks, six cycles of CAR T-cell infusions were performed in a past tumor site labeled T1 in the MRI scans below (horizontal view). Interestingly, while the cancer continued to progress near past tumor sites that did not receive the treatment (T2 and T3; sagittal view), the CAR T-cell injection site (T1) did not show evidence of disease recurrence 50 days post-surgery. Spinal tumors started to emerge at that point, so ten additional cycles of CAR T-cell infusions were performed into the ventricles of the brain with the hopes that the effects of the therapy would not be as localized. [Ventricles are interconnected cavities within the brain that take part in circulating cerebrospinal fluid throughout the central nervous system (i.e. the brain and spinal cord)]. Lo and behold, at the end of the course of the treatment, no tumors were detected on MRI and PET scans! The patient was able to return to his normal day-to-day activities and there were no disease recurrences up until 7.5 months from the start of the CAR T-cell therapy, and even then, the tumors that emerged were not in the same locations as before.

At the heart of the idea behind CAR T-cell therapy is the fact that our bodies already contain a defense mechanism against infection and other types of disruptions. Yes, I am indeed talking about our resident white blood cells, specifically one type called T-lymphocytesor T-cells. Even though we have these potent fighter cells, solid tumor cancers such as glioblastoma can be difficult to combat because tumors create animmunosuppressive environment around them. Tumor cells can express certain proteins on their surface that, when bound to complementary receptor proteins on the surface of a T-cell, render the T-cells impotent thus suppressing the immune response (see PD-L1 as depicted in yellow and PD-1 as depicted in orange, respectively, in Figure 1).

Figure 1: a suppressed T-cell due to PD-L1 protein and PD-1 receptor interaction

Under normal circumstances (that is, when healthy cells express PD-L1 protein on their surface), this protein-receptor interaction can be beneficial because we do not want our T-cells to go unchecked and attack normal cells indiscriminately; that could lead to autoimmune diseases and other undesirable consequences. But when you need to attack tumor cells, inhibiting this protein interaction can boost the immune system’s ability to destroy tumor cells, hence why “checkpoint inhibitors” such as PD-L1 and PD-1 inhibitors have been proposed and tested as effective immunotherapy options for cancer. Assuming that we’ve taken care of the immunosuppression due to PD-L1 and PD-1 by administering checkpoint inhibitors to the patient, the next strategic move is to make it easier for T-cells to target tumor cells while sparing healthy cells. This is where CAR T-cell therapy comes into play because it takes a slightly different approach to enhance the ability of T-cells to specifically recognize and fight tumor cells.

The biological trick: How are T-cells genetically engineered to enhance their ability to recognize and fight tumor cells?

First, the patient’s blood is collected with the help of an apheresis machine that can separate the white blood cells and send the rest of the blood back to the patient. The next step is to take the collected T-cells and, in a lab setting, insert into them a gene that encodes a chosen chimeric antigen receptor (CAR)which will specifically recognize and bind to a protein that is ideally only found on the tumor cells of interest. Once the T-cells are genetically engineered and multiplied, they get infused back into the patient and wreak havoc on the targeted tumor cells. In this context, chimeric is just referring to the fact that the CAR gene delivered into the T-cells is a hybrid construct put together using different pieces of genetic material.

The optimal choice of CAR will be different depending on which cancer type you would like the T-cells to be sensitive to. For instance, Dr. Ezra Cohen’s research group at UCSD’s Center for Precision Immunotherapy is focusing on engineering a CAR that recognizes protein ROR1 expressed in ovarian, pancreatic, head-neck, and triple-negative breast cancer tumors. ROR1 is a protein that is important during embryonic development, but for the most part disappears in adult tissue unless it reappears in the aforementioned cancer types. This is a crucial point that led the research team to identify ROR1 as a viable target for their CAR because, if ROR1 was a protein expressed widely throughout the body in adulthood rather than specifically in the tumors, their engineered CAR T-cells could cause more harm than good.

Super CAR T-cells

As fellow Neuwriter Caroline Sferrazza has deftly explained in previous posts, the CRISPR-Cas9 gene editing system is science’s new obsession, not least because of its many powerful applications (A Crisp(r) Explanation of Biology’s Coolest New Tool). It is a technological development that will certainly shape immunotherapy in the years to come, and even in the short term, it has inspired scientists to engineer more powerful CAR T-cells. Using CRISPR, scientists can now edit out the gene for PD-1 or other cell surface receptors on CAR T-cells. This will eliminate the need to administer checkpoint inhibitors to cancer patients because the CAR T-cells won’t have the receptors that tumor cell surface proteins need to bind to in order to induce immunosuppression.

Super CRISPR-edited CAR T-cell or not, this new advancement in immunotherapy is another way in which I am reminded that science will continue to astound us with what it can allow us to accomplish when applied wisely.

*A very special thank you to Dr. Ezra Cohen for a fascinating interview on CAR T-cell therapy.